The mitochondrial citrate carrier, SLC25A1, drives stemness and therapy resistance in non-small cell lung cancer.
The mitochondrial citrate carrier, SLC25A1, drives stemness and therapy resistance in non-small cell lung cancer.
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线粒体柠檬酸盐载体SLC25A1驱动非小细胞肺癌的干性和治疗抗性。
DOI：
10.1038/s41418-018-0101-z
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发表时间：
2018-07
影响因子：
12.4
通讯作者：
Avantaggiati ML
中科院分区：
文献类型：
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作者：
Fernandez HR;Gadre SM;Tan M;Graham GT;Mosaoa R;Ongkeko MS;Kim KA;Riggins RB;Parasido E;Petrini I;Pacini S;Cheema A;Varghese R;Ressom HW;Zhang Y;Albanese C;Üren A;Paige M;Giaccone G;Avantaggiati ML
治疗耐药是晚期非小细胞肺癌（NSCLC）的临床挑战，这仍然是一种无法治愈的疾病。越来越多的证据表明，癌症启动细胞或癌症干细胞（CSCs）提供了一个缓慢生长的休眠细胞群的储存库，这些细胞具有肿瘤启动和无限的自我更新能力，这些能力被传统疗法遗留下来，重新点燃治疗后复发和转移性传播。CSCs扩增所需的代谢途径尚未完全确定，但对它们的理解可能会开辟新的治疗机会。我们在这里表明，肺CSCs依赖于氧化磷酸化，通过线粒体柠檬酸转运体SLC25A1的活性来产生能量和存活。我们证明SLC25A1在维持CSCs的柠檬酸盐线粒体库和氧化还原平衡中起关键作用，而其抑制会导致活性氧的积累，从而抑制CSCs的自我更新能力。此外，在不同的患者源性肿瘤中，对顺铂或表皮生长因子受体（EGFR）抑制剂治疗的耐药是通过slc25a1介导的线粒体活性的实现和干细胞表型的诱导获得的。因此，在体外和动物模型中，新发现的特异性SLC25A1抑制剂与顺铂或EGFR抑制剂联合治疗是合成致死的，并恢复对这些药物的抗肿瘤反应。这些数据具有潜在的临床意义，因为它们揭示了耐药肺CSCs的代谢脆弱性，鉴定了一种新的SLC25A1抑制剂，最后，提供了第一个证据，表明阻断SLC25A1活性的药物与选定的传统抗肿瘤药物联合使用时，会产生治疗益处。
Therapy resistance represents a clinical challenge for advanced non-small cell lung cancer (NSCLC), which still remains an incurable disease. There is growing evidence that cancer-initiating or cancer stem cells (CSCs) provide a reservoir of slow-growing dormant populations of cells with tumor-initiating and unlimited self-renewal ability that are left behind by conventional therapies reigniting post-therapy relapse and metastatic dissemination. The metabolic pathways required for the expansion of CSCs are incompletely defined, but their understanding will likely open new therapeutic opportunities. We show here that lung CSCs rely upon oxidative phosphorylation for energy production and survival through the activity of the mitochondrial citrate transporter, SLC25A1. We demonstrate that SLC25A1 plays a key role in maintaining the mitochondrial pool of citrate and redox balance in CSCs, whereas its inhibition leads to reactive oxygen species build-up thereby inhibiting the self-renewal capability of CSCs. Moreover, in different patient-derived tumors, resistance to cisplatin or to epidermal growth factor receptor (EGFR) inhibitor treatment is acquired through SLC25A1-mediated implementation of mitochondrial activity and induction of a stemness phenotype. Hence, a newly identified specific SLC25A1 inhibitor is synthetic lethal with cisplatin or with EGFR inhibitor co-treatment and restores antitumor responses to these agents in vitro and in animal models. These data have potential clinical implications in that they unravel a metabolic vulnerability of drug-resistant lung CSCs, identify a novel SLC25A1 inhibitor and, lastly, provide the first line of evidence that drugs, which block SLC25A1 activity, when employed in combination with selected conventional antitumor agents, lead to a therapeutic benefit.
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影响因子：
--
作者：
Kolukula VK;Sahu G;Wellstein A;Rodriguez OC;Preet A;Iacobazzi V;D'Orazi G;Albanese C;Palmieri F;Avantaggiati ML
通讯作者：
Avantaggiati ML
影响因子：
64.8
作者：
Jiang L;Shestov AA;Swain P;Yang C;Parker SJ;Wang QA;Terada LS;Adams ND;McCabe MT;Pietrak B;Schmidt S;Metallo CM;Dranka BP;Schwartz B;DeBerardinis RJ
通讯作者：
DeBerardinis RJ
影响因子：
4.1
作者：
NEWSHOLME, EA;SUGDEN, PH;WILLIAMS, T
通讯作者：
WILLIAMS, T
影响因子：
12.4
作者：
Eramo, A.;Lotti, F.;De Maria, R.
通讯作者：
De Maria, R.
影响因子：
4.2
作者：
Palmieri, Ferdinando
通讯作者：
Palmieri, Ferdinando